The inhibition of platelet activation and aggregation, or antiplatelet therapy, has been recognized as a means to impact coagulation and inflammation in a way that conventional anticoagulant therapy is unable to (Bhatt, D. L.; Topol, E. J. Nat Rev Drug Disc 2003, 2, 15-28). As such, inhibitors of platelet activation and aggregation are substances that are useful during percutaneous coronary intervention (PCI) and other catherization techniques in order to reduce bleeding complications, and in the treatment of acute coronary syndromes (ACS) and clotting disorders in general. One class of antiplatelet agents is inhibitors of the P2Y12 receptor, a G-protein coupled purinergic receptor which is an important component of platelet activation (Dorsam, R. T.; Kunapuli, S. P. J Clin Invest 2003, 113, 340-345). In particular, cangrelor ([dichloro-[[[(2R,3 S,4R,5R)-3,4-dihydroxy-5-[6-(2-methylsulfanylethylamino)-2-(3,3,3-trifluoropropylsulfanyl)purin-9-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl]methyl]phosphonic acid; the mixed mono(anhydride) of N-[2-(methylthio)ethyl]-2-[(3,3,3-trifluoropropyl)thio]-5′-adenylic acid with dichloromethylenebisphosphonic acid) is a reversible inhibitor of the P2Y12 receptor which is under clinical evaluation for its potential use in PCI.
Cangrelor (also referred to as ARC69931MX) is a synthetic analogue of adenosine triphosphate (ATP) and a potent antagonist of the P2Y12 receptor with a pIC50 of 9.35 (Chattaraj, S. C. Curr Opin Investig Drugs 2001, 2, 250-55; Diaz-Ricart, M. Drugs Future 2008, 33, 101-110; U.S. Pat. Nos. 5,721,219 and 5,955,447). It is being developed as the sodium salt.
In light of the medical and therapeutic applications of cangrelor, it is essential that pharmaceutical formulations comprising cangrelor maintain high levels of purity. Formulations comprising cangrelor are compounded formulations, e.g., cangrelor undergoes a compounding process following its synthesis so that it is usable and stable for medical and therapeutic applications. This compounding process typically includes mixing the drug with excipients in a solution, followed by aseptic filtration and lyophilization.
Impurities such as, but not exclusively, dichloromethylenebisphosphonic acid, N-[2-(methylthio)ethyl]-2-[(3,3,3-trifluoropropyl)thio]-5′-adenylic acid (a product of the hydrolysis of the dichloromethylenebisphosphonate group on cangrelor), its bis(anhydride) with dichloromethylenebisphosphonic acid, N-[2-(methylsulfinyl)ethyl]-2-[(3,3,3-trifluoropropyl)thio]-5′-adenylic acid monoanhydride with dichloromethylenebisphosphonic acid and 2-(3,3,3-trifluoropropylthio)-N-(2-(methylthio)ethyl)-adenine and others may be generated during the synthesis and the compounding process. These compounds are represented in their neutral form but are generally present as salts.
Methods have been developed that minimize the generation of impurities during cangrelor synthesis. However, impurities produced during the compounding process remain problematic. It has been shown that various compounding processes can result in formulations in which a significant proportion of cangrelor has been degraded, which may affect not only product stability and shelf-life, but ultimately the ability to control dosage during administration to patients. In addition, because the pharmacological impact of the degradation products has not been evaluated in clinical settings, it is critical to maintain them to a level at or below the levels used in clinical evaluation. Therefore, development of a compounding process for formulating cangrelor that consistently generates formulations having low levels of impurities is desirable.
The invention disclosed herein addresses the need for pharmaceutical formulations comprising high purity cangrelor as the active ingredient and methods for producing the same, where low levels of impurities are consistently achieved and maintained.